Approximately 800,000 persons in the U.S. suffer an acute stroke each year. There presently is no neuroprotective agent that can be given to patients with acute stroke, and stroke is the third leading cause of death. The costs for rehabilitation of patients that survive a stroke is greater than $40 billion per year in the U.S. The reason that an effective neuroprotective drug has not been developed so far, despite intensive efforts in the pharmaceutical industry, is that most of the drugs do not cross the blood-brain barrier (BBB). Neurotrophins are potential large molecule neuroprotectives but these, too, do not cross the BBB. The present research plan aims at a merger of neurotrophin drug discovery and BBB drug targeting technology, so that a recombinant neurotrophin can be re-formulated as a genetically engineered fusion protein to enable transport of the neurotrophin through the BBB in vivo following delayed intravenous administration in humans. Such a drug will cause neuroprotection in stroke patients following intravenous administration, because the neuroprotective agent will have been specifically designed to cross the BBB. Prior work has produced AGT-120, which is a genetically engineered fusion protein wherein the neurotrophin variant is fused to a targeting ligand that undergoes receptor-mediated transport across the BBB in vivo. This BBB transport vector has been previously genetically engineered to enable use in humans without immunological reaction. The fusion protein is a bi-functional molecule that not only crosses the BBB, but also binds to the specific neurotrophin receptor on neurons to cause neuronal neuroprotection. The following will be done in the proposed work: (i) pharmacology/toxicology of AGT-120 under Good Laboratory Practice conditions, (ii) submission of an IND to the FDA for single intravenous administration of AGT-120 to patients with acute stroke, (iii) phase l-ll clinical trial to examine safety, tolerability, and pharmacokinetics, and to explore the efficacy of intravenous AGT-120 within 5 hours of an acute stroke. AGT-120 is the first large molecule neuroprotective that has been specifically formulated to cross the BBB in humans following intravenous administration. [unreadable] [unreadable] [unreadable]